22-halo-20-spirox-4-ene-3, 21-diones and process for preparation



United States Patent G F 3,083,200 ZZ-HALO-Z-SPIROX-4-ENE-3,21-DIONES AND PROCESS FOR PREPARATION Arthur A. Patchett, Metuchen, and Frederick F. Giarrusso,

Elizabeth, N.J., assignors to Merck & (30., Inc., Rah- Way, N.J., a corporation of New Jersey No Drawing. Filed June 27, 1960, Ser. No. 38,710 Claims. (Cl. 260-23957) This invention is concerned generally with novel steroids and processes of preparing the same. More particularly, it relates to novel 22-halogen-20-spirox-4-ene- 3,21-diones, to the 7a-alkanoylthio-derivatives thereof, and to closely related compounds, which steroids possess useful therapeutic properties as aldosterone inhibitors. This invention also relates to pharmaceutical compositions containing these novel steroid compounds.

The name ZO-spiroxane is used to designate com pounds having the following ring structure:

The novel "22-halogen-20-spirox-4-ene-3,21-diones which form the subject of the present invention accordingly are compounds having the following structural formula:

wherein the dotted lines between carbons 1-2 and'6-7 indicate that a double bond may be present in these positions, and wherein R refers to hydrogen or methyl, X refers to hydrogen or a keto or hydroxy substituent, Y refers to hydrogen or a lower alkanoylthio radical, Z refers to hydrogen or halogen, and Z refers to a halogen atom. This invention also contemplates the lower alkyl, cyclohexyl and benzyl 3-enol ethers of compounds having the above structure. Among the radicals comprehended by the expression lower alkanoyl are forrnyl, acetyl, propionyl, butyryl, valeryl, hexanoyl, heptanoyl, octanoyl and branched-chain isomers thereof, said alkanoyl radicals being the acyl radicals of alkanoic acids containing fewer than nine carbon atoms.

These novel steroids block the salt-retaining effects of aldosterone and other salt-retaining steroids so as to be useful in the treatment of diseases such as congestive heart failure, nephrosis and cirrhosis of the kidney in which aldosterone secretion is increased.

In preparing our novel chemical compounds, the starting material utilized is a 20-spirox-4-ene-3,2l-dione which 3,083,200 Patented Mar. 26, 1963 may be identified by the following-structural formula:

wherein the dotted line between carbon atoms 9 and 11 indicate that a double bond may be present in this position, and wherein X refers to hydrogen or an hydroxy substituent. However, it is clear to those skilled in the art that starting materials having other substituents in the above ring may be similarly converted to thedesire'd end products.

In a specific embodiment of our invention, 20-spirox- 4-ene-3,21-dione is converted into 3-ethylenedioxy-20- spirox-S-ene-Zl-one, which has the structure given below, for example, by exchange dioxolanation using butanone dioxolane in the presence of an acid catalyst such as p toluenesulfonic acid.

Upon treatment of 3-ethylenedioxy-20-spirox-5-ene-2l-' vThe 3-ethylenedioxy-ZZ-fiuoro-20-spirox-5-ene-2l-one,

which has the following structure:

is prepared by contacting 3-ethylenedioxy-22methox alyl-ZO-spi-rox-S-ene-Zl-one with an alkali metal alkoxide to form the enolate, which on reaction with pe'rchloryl 3,oss,2oo

fluoride gives the 22-fluoro-22-alkoxalyl-derivative. The latter compound is then converted into 3-ethylenedioxy- 22rfluoro-20-spirox-5-ene-21-one on treatment with an alkali metal alkoxide.

The 3-ethylenedioxy-22-bromo-20-spirox-5-ene-2l-one, which has the following structure:

With

is formed by treating 3-ethylenedioxy-22-methoxalyl-20- spirox-5-ene-21-one first with bromine in the presence of an organic base such as pyridine, and then with an alkali metal alkoxide.

The 3-ethylenedioXy-22-chloro-2(}-spiroX-5-ene-2l-one, which has the following structure:

[fl O5 wherein 2' stands [for a halogen atom. j

The 22-halo-20-spirox-4-ene-3,2l-dione is converted to 22-fluoro-20-spirox-l,4-diene-3,21-dione .by dehydrogenation with selenium dioxide.

Heating 22-halo-20-spirox-4-ene-3,21-di0ne with chloranil in a solvent such' as t-butanol, gives 22-halo-20- spirox-4,6-diene-3,21-dione which when heated With a lower thioalkanoic acid gives:

wherein Z stands for ahalogen atom.

The latter reaction proceeds fairly rapidly at elevated temperatures, such as those in excess of 50 C. and can be carried out optionally under the influence of ultraviolet light. In carrying out the addition reaction with lower boiling thioalkanoic acids, such as thioacetic acid, it is convenient to conduct the reaction at the reflux temperature of the reaction mixture; whereas with higher boiling thioallcanoic acids it is convenient to conduct the reaction at a temperature of about 90-100 'C. Heating periods of up to a few hours are suificient to achieve substantialconversion to the desired reaction products. Typically, the desired compound is obtained in a satisfactory state of purity by direct filtration of the cooled reaction mixture, preceded, where necessary by removal of excess thioalkanoic acid. If desired, however, the reaction product can be purified by chromatography using adsorbents such as silica gel or acid-washed alumina, followed by elution with mixtures of ethyl acetate in benzene.

The addition of thioalkanoic acids to the 6,7-double bond of the starting materials employed in the practice of this invention proceeds under steric influences such that of the stereoisomers formed, one is obtained in predominant amount, which in each case, has been characterized herein as possessing the a-configuration of the 7-acylthio-group. However, the designated configuration of the 7-acylthio group is based upon an analysis of molecular rotation data presently appearing in the chemical literature, and is therefore not to be interpreted except in relation to the state of the art presently known to organic chemists. It will be apparent that no part of the specification will be materially defective if it should later be established that the configuration is the opposite of that deducible from data presently available to workers in the field.

In accordance with this invention, but starting with the 2-tl spirox-4-ene-l lfi-ol-3,21-dione instead of ZO-spirox- 4-ene-3,21-dione, and following the above described procedures, there is'obtained as end products having useful therapeutic properties as aldosterone inhibitors the 22- halo-20-spirox-4-ene-l1,3-ol-3,21-dione, 22-halo-20-spirox- 1,4-diene-l1fi-ol-3,21-dione, and 7m-lower alkanoylthio- 22 halo 20 spirox-4-ene-11fi-ol-3,21-dione. The latter compounds may be converted to the 22-halo-20-spirox- 4-ene-3,11,21-trione, 22-hal0-20-spirox-l ,4-diene-3,1 1,21- trione, and la-lower alkanoylthio-22-ha1o-20-spirox-4-ene- 3,11,21-trione respectively on oxidation with chromic acid.

The 2a-methyl-22-fluoro-2Q-spirox-4-ene-3,2l-dione is prepared from 22-fluoro-20-spirox-4-ene-3,21-dione by reaction of the latter compound with an alkyl oxalate and sodium alkoxide to form' thesodium enolate of the 2- alkoXyoxalyl-derivative, which when methylated with methyl iodide, followed by removal of the alkoxyoxalyl group, using sodium alkoxide, gives 2a-methyl-22-fluoro- 20-spirox-4-ene-3,2l-dione. V

The 2a-methyl-22-fluoro-20-spirox-4-ene-3,2l-dione is converted into the 2-methyl-22-fluoro-20-spirox-1,4-diene- 3,1-dione by dehydrogenation with selenium dioxide.

The 2u-methyl-22-fiuoro'20-spirox-4-ene-3,2l-dione is converted into the 7m-acetylthio-2a-rnethyl-22-fluoro-20- spirox-4-ene-3,2l-dione by first heating with chloranil in a solvent such as t-butanol to give Zoc-DIEthYl-ZZ-flUOI'O-ZO- spirox-4,6-diene-3,21-dione, and then reacting the latter compound with thioacetic acid to produce 7a-acetylthio- 2a-methyl-22-fluoro-20-spirox-4-ene-3,21-dione.

The novel 9a,22-difluoro-20-spirox-4-ene-1 Idol-3,21- dione is prepared from the 20-spirox-4,9(l1)-3,21-dione by the following steps:

The 20-spirox-4,9(11)-3,21-dione is reacted with butanone dioxolane and p-toluenesulfonic acid monohydrate to giver3 ethylenedioxy-20-spirox-5,9(1l)-diene-21-one.

'The latter compound is converted into the 3-ethylenedioxy 22-methoxalyl-ZO-spirox-S,9( 1 1 -diene-21-one upon treatment with sodium hydride and dimethyl oxalate.

The 3-ethylenedioxy-22-fluoro-20-spirox-5,9 l 1)-diene-21- one is prepared by contacting 3-ethylenedioxy-22-methoxaly1-20-spirox-5,9(ll)-diene-2l-one with sodium ethoxide to form the enolate which on reaction with perchloryl fluoride, gives a product which on subsequent treatment with sodium ethoxide forms 22-fiuoro-20-spirox- 4,9( ll)-diene-3,21-dione. The latter compound is treated with N-bromosuccinimide to give 9u-bromo-22-fluoro-20 spirox-4-ene-l1B-ol-3,2l-dione, which on heating with potassium acetate in absolute ethanol forms 22-fluoro-20- spirox 4 ene-3,2l-dione-9,llit-oxide. The latter compound is then reacted with anhydrous hydrogen fluoride to afiord 9a,22-difluoro-20-spirox-4-ene-11;8-ol-3,21-dione.

The 9u,22-difluoro-20-spirox 4-ene-11fi-ol-3,21-dione is converted into 20-spirox-9a,22-difluoro-1,4-diene-115-01- 3,2l-dione by dehydrogenation with selenium dioxide.

The 7a-acetylthio-9a,2Z-difluoro-ZO-spirox-4-ene-l -01- 3,21-dione is prepared from 9u,22-difluoro-20-spirox-4- ene-11/3-ol-3,2l-dione by heating the latter compound with chloranil to give 9a,22-difluoro-20-spirox-4,6-diene-11,8- o1-3,2l-dione, which is then reacted with thioacetic acid to produce 7a-acetylthio-9a,22-difluoro-20-spirox-4-enellB-ol-3,21-dione.

The 911,22 difluoro--spirox-4-ene-l1fl-ol-3,2l-dione, 7a acetylthio-9a,22-difluoro-20-spirox-4-ene-1lfi-ol-3,2ldione and 20-spirox-9a,22-difluoro-1,4-diene-1Iii-018,21- dione are oxidized with chromic acid in pyridine to give the corresponding ll-keto-steroid.

The 2a methyl-9a,22-difluoro-20-spirox-4-ene-11,8-01- 3,2l-dione is prepared from 22-fluoro 20 spirox-4-ene- 3,2l-dione-9,l1[3-oxide by reaction of the latter compound with an alkyl oxalate and sodium alkoxide to form the sodium enolate of the 2-alkoxyoxalyl derivative, which when methylated with methyl iodide, followed by removal of the alkoxyoxalyl group using a sodium alkoxide, gives the 2a-methyl-22-fiuoro-20-spirox-4-ene-3,21-dione, 9,11 3- oxide. The latter compound is then reacted with anhydrous hydrogen fluoride to form the 2oz-methy1-9u,22- difluoro-20-spirox-4-ene-11B=ol-3,2l-dione.

The 7a-acetylthio-2u-methyl-92z,22-difiuoro-20-spirox-4- ene-llBol-3,2l-dione is prepared from 2a-methyl-9a,22- difluoro-20-spirox-4-ene-1lfi-ol-3,2l-dione by heating the latter compound with chloranil to give 2u-methyl-9u,22- difiuoro 2O spirox-4,6-diene-ll,B-ol-3,21-dione which is then reacted with thioacetic acid to produce 7a-acetylthio- 2a methyl-9a,22-difluoro 20 spirox-4-ene-l1fi-ol-3,21- dione.

The 20: methyl-90:,22-difluoro-20-spirox-4-ene-115-01- 3,21-dione is converted into 2-methyl-9a,22-difluoro-20- spirox-1,4 diene 11fi-ol-3,2l-dione by dehydrogenation with selenium dioxide.

The 2a methyl-9a,2Z-difiuoro-20-spirox-4-ene-1Idol- 3,21-dione, 7a-acetylthio 2a methyl-9a,22-difluoro-20- spirox 4 ene-llB-ol-3,21-dione and 2 methyl-9a,22-difluoro-ZO-spirox-1,4-diene-11 8-ol-3,2l-dione are oxidized with chromic acid in pyridine to give the corresponding 1 l-keto-steroid.

A further embodiment of our invention comprises novel pharmaceutical compositions containing these 22-halo-20- spirox-4-ene-3,21-diones exemplified in the foregoing structures. A preferred embodiment of our invention comprises pharmaceutical compositions containing these 22- halo-20-spirox-4-ene-3,2l-dione compounds combined with diuretics such as chlorothiazide, hydrochlorothiazide, and related compounds.

The following examples illustrate methods of carrying out the present invention but it is to be understood that these examples are given for purposes of illustration and not of limitation.

Example 1 A mixture of 1.850 g. of 20-spirox-4-ene-3,2l-dione, 100 cc. of butanone dioxolane (distilled from lithium aluminum hydride) and 60 mg. of p-toluenesulfonic acid monohydrate is distilled for 4% hours through a Vigreux column. The residue is partitioned between 5% aqueous Cx [BOG Example 2 Dimethyl oxalate (3.5 grams) is dissolved in 30 cc. of benzene. The solution is then azeotropically dried to a volume of 25 cc. Sodium hydride (1.050 g.), as a 52.7% dispersion in oil, is added. A slight reaction occurs. To this grey suspension is added 687 mg. of 3-ethylenedioxy 20 spirox-5-ene-21-one. The reaction mixture is held at 40 C. overnight with magnetic stirring. It is then diluted with an equal volume of ether and centrifuged. The precipitate is washed three times with an equal volume of ether. The sodium enolate is then covered with about 10 cc. of benzene and a saturated solution of sodium dihydrogen phosphate (pH 4) is added as quickly as possible. The separated aqueous layer is extracted two more times With ether The combined organic layers are dried and concentrated in vacuo. The product is recrystallized several times from a mixture of ether and petroleum ether to give 3ethylene-dioxy-22- [methoxalyl]-20-spirox5-ene-2l-one, which has the fol lowing structure:

Example 3 A solution of mg. of 3-ethylenedioxy-22-[methoxalyl]-20-spirox-5-ene-2l-one, dissolved in 6 cc. of pyridine, is cooled to 0 C. Sodium ethoxide (26 cc. of 1 M sodium ethoxide in ethanol) is then added and the resultant solution is flushed with nitrogen for about 2 minutes. With operations conducted behind a shield, perchloryl fluoride is then bubbled into the reaction mixture for 15 minutes at 0 C. and the system is again flushed with nitrogen for about two minutes. The mixture is then poured into water and extracted with ether. The combined ether layers are washed with water, and dried, and the solvent evaporated at room temperature using a rotary evaporator. Final traces of solvent are removed under vacuum.

The residue is dissolved in 4 cc. of absolute ethanol, and 1 cc. of 1 M sodium ethoxide in ethanol is added. The solution is then allowed to stand at room temperature for 2 hours. A precipitate forms. The reaction mixture is carefully acidified, maintaining the temperature at 0 C. and then poured into water. The vmixture MN F Example 4 Seventy-three milligrams of 3-ethylenedioxy-22-fluoro- 20-spirox-5-ene-2l-one is dissolved in 4 cc. of acetone and 5 mg. of p-toluenesulfonic acid monohydrate in 1 cc. of acetone is added. The solution is allowed to stand overnight at room temperature. -It is then diluted with wateran'd extra'cted'three' times with ether. The combined ether extracts are washed with water, dried and concentrated in'vacuo. The residue is chromatographed over acid-washed alumina and eluted with mixtures of chloroform and 'ether. Recrystallization from a mixture of methylene chloride and ether aifords the substantially pure 22-fluoro-20-spirox-4-ene-3,2l-dione, M.P.

A suspension of 22-fluoro-20-spirox-4-ene-3,2l-dione (11.1 g.) and chloranil (24.3 g.) in 360 ml. of dry tbutanol is heated under reflux forthree hours, protected by a blanket of nitrogen. The solvent is removed and the residue is dissolved in chloroform. The resulting solution is washed with aqueous sodium bisulfite solution and then with 5% potassium hydroxide followed by water. The solution is dried over sodium sulfate and concentrated under reduced pressure to give 22- fluoro-20-spirox-4,6-diene-3,21-dione, which has the following structure:

OT- Nw F 0 Example 6 A solution of 80 mg. of 22fluoro-20-spirox-4,6-diene- 3,2.1-dione in 1.0 ml. of thioacetic acid is heated under reflux on a steam bath for a period of /2 hour. Tn'tura: tion with ether afiords crystals which, after two recrystallizations from a mixture of acetone and hexane, gives 5.0. mg- "of pure 7a-acetylthio-22-fluoro-20-spirox-4-ene-' 3,2l-dione,which has the following formula:

To 8.0 g.of 22-fluoro-20-spirox-4-ene-3,2l-dione suspended in 100 ml. *of t-butyl alcohol is added 3.2 g. of dornrnercial"(95%) sodium methylate. To this mixture under nitrogen is added 5 ml. of diethyl oxalate, and the mixture is then stirred under nitrogen for 6 hours. Complete solution occurs and the product precipitates withinlO minutes. Addition of ether followed by filtration gives 13 g. of the sodium enolate, which is a powder, soluble in Water but insoluble in dilute acid.

A mixture'of. the crude sodium enolate, 13 g. of anhydrous potassium carbonate, 300 ml. of acetone and 50 ml. of methyl iodide is refluxed for 20 hours, filtered While hot and the filtrate concentrated to a small volume. A large amount of water is added to the concentrate which is then extracted with ethyl acetate. The extract is washed with saturated sodium chloride solution, dried andjtreated-with activated carbon. After evaporation 7.8 g. of a pale yellow residue is obtained.

To this residue, dissolved in 250 ml. of absolute alcoho], is added 1.0 g. of 95% 'NaOCH The mixture is then allowed to stand at room temperature for 4 hours. After the addition of a few drops of acetic acid'and 20 ml. of water, the methanol is' removed under reduced pressure at a temperature not exceeding 35 C. The ethyl acetate extract of the mixture is washed to neutrality with a saline solution, dried, and decolor-ized with activated carbon." Evaporation leaves 5.7 g. ofthe crude Za' methyI 22 4 fluoro 20. spirox 4 ene 3,21- dione, which has the following structure:

Example 8 ous sodium bicarbonate, ammonium sulfide, dilute amacetone and ether gives 2-rnethyl-22-fiuoro-20-spirox-1,4- diene-3,21-dione, which has the following structure:

Example 9 A suspension of 2a-methyl-22-fluoro-20-spirox-4-ene-3, 21-dione (11.1 g.) and chloranil (24.3 g.) in 360 ml. of dry -t-butanol is heated under reflux for three hours, protected by a blanket of nitrogen. The solvent is removed and the residue is dissolved in chloroform. The resulting solution is washed with 10% aqueous sodium bisulfite solution and then with potassium hydroxide followed by water. The solution is dried over sodium sulfate and concentrated under reduced pressure to give 2a-methyl-22- fluoro-20-spirox-4,6-diene-3,ZI-dione, which has the r01- lowing structure:

O=l NW F Example A solution of 80 mg. of 2tat-methyl-22-fiuor0-2O-spirox- 4,6-diene-3,2l-dione in 1.0 m1. of thioacetic acid is heated under reflux on a steam :bath for a period of /2 hour. Excess thioacetic acid is evaporated in a stream of nitrogen. Irituration with ether afiords crystals which, after two recrystallizations from a mixture of acetone and hex- 311e, gives 7a-acetylthio-2u-methyl-22-fluoro-20-spirox-4- ene-3,2l-dione, which has the following structure:

1 t3 1 1 diene-Z Lone, which has the .following structure:

Example 12 Dimethyl oxalate (3.5 gms.) is dissolved in 30 cc. of benzene. The solution is then azeotropically dried to a volume of 25 cc. Sodium hydride (1.050 g.), as a 52.7% dispersion in oil, is added. A slight reaction occurs. To this grey suspension is added 687 mg. of 3-ethylenedioxy- 20-spirox-5,9(11)-diene-21-one. The reaction mixture is held at 40 C. overnight with magnetic stirring. It is then diluted with an equal volume of ether and centrifuged. The precipitate is washed three times with an equal volume of ether. The sodium enolate is then covered with about 10 cc. of benzene and a saturated solution of sodium dihydrogen phosphate (pH 4) is added as quickly as possible. The separated aqueous layer is extracted two more times with ether. The combined organic layers are dried and concentrated in vacuo. The product is recrystallized several times from a mixture of ether and petroleum ether to give 3-ethylenedioxy 22 [meth-oxalyl] -20-spirox-5,9 (11)-diene-21-one, which has the following structure:

O l O Example 13 A solution of mg. of 3-ethy1enedioxy-22-[methoxalyl]-20-spirox-5,9(11)-diene-2l-one, dissolved in 6 cc. of pyridine, is cooled to 0 C. Sodium ethoxide (26 cc. of 1 M sodium ethoxide in ethanol) is then added and the resultant solution is flushed with nitrogen nor about 2 minutes. With operations conducted behind a shield, perchloryl fluoride is then bubbled into the reaction mixture for 15 minutes at 0 C. and the system is again flushed with nitrogen for about two minutes. The mixture is then poured into water and extracted with ether. The combined ether layers are washed with water and dried, and the solvent evaporated at room temperature using a rotary evaporator. Final traces of solvent are removed under vacuum.

The residue is dissolved in 4 cc. of absolute ethanol, and 1 cc. of 1 M sodium ethoxide in ethanol is added. The solution is then allowed to stand at room temperature for 2'hours. A precipitate forms. The reaction mixture is carefully acidified, maintaining the temperature at 0 C., and then poured into water. The mixture is extracted with ether and the ether extract is dried and concentrated in vacuo to give a residue of the crude, 3-ethylenedioxy- 22-fluoro-20-spirox-5,9(11)-diene-21-one, which is suitable for the next step of the synthesis without further purification.

Example 14 Example 15 To a mixture of 620 mg. of 22-fiuoro-20-spirox-4,9(11)- diene-3,2l-dione and 330 mg. of N-bromosuccinimide in 10 ml. of dioxane and 3.2 ml. of water cooled to 10 C. is added 1.8 ml. of cold 1 M aqueous perchloric acid. The mixture is stirred at 15 C. for 3 hours. Excess N-bromosuccinimide is destroyed by addition of aqueous sodium thiosulfate and most of the dioxane is removed in vacuo. About 30 ml. of water is added and the product is filtered, washed with water, and dried in air to give 9a-bromo-22-fluoro-2O-spirox-4-ene-11,8-01 3,21 dione which has the following formula:

Example 16 12 from ethyl acetate-ether to'give 22-fluoro-20-spirox-4-ene- 3,21-dione-9,11e-0xide, which has the following structure:

Example 1 7 To a solution of 200 mg. of 22-fluoro-20-spirox-4-ene- 3,2l-dione-9,llB-oxide in 2 ml. of chloroform and 2 ml. of tetrahydrofuran in a polyethylene bottle at -60 C. is added 2 ml. of a 2:1 (by weight) mixture of anhydrous hydrogen fluoride and tetrahydrofuran. After 4 hours at 10 C. the mixture is cooled to 60 C. and cautiousl added to a stirred mixture of 30 ml. of 25% aqueous potassium carbonate and 25 ml. of chloroform kept at 5 C. The aqueous phase is further extracted with chloroform and the latter phase is washed with water and dried over magnesium sulfate. The residue on crystalliza-tion from acetone-ether gives '9u,22-diflll0IO-2Q- spirox-4-ene-l1fl-0l-3,2'l-dione, which has the following structure:

Example 18 To mg. of 901-22-difluoro-20-spirox-4-ene-llfl-ol 3,21-dione in 5 m1. of t-butanol and 0.1 ml. of acetic acidis added 50 mg. of selenium dioxide. The mixture is refluxed under nitrogen for 18 hours; then 50mg. of selenium dioxide is added and the mixture is refluxed an additional 24 hours. The product is filtered, and the filtrate evaporated to dryness. The residue is extracted with ethyl acetate and the extract is washed successively with aqueous sodium bicarbonate, ammonium sulfide, dilute ammonia water, water, dilute hydrochloric acid and water, and then dried over magnesium sulfate. The extract is treated with activated charcoal and then concentrated to dryness. Crystallization of the residue from a mixture of acetone and ether gives 20-spirox-9u,22-diiluoro-1,4-diene-11fl-ol-3,21-dione, which has the following structure:

3,21-dione (11.1 g.) and chloranil (24.3 g.) in 360 m1. of dry t-butanol is heated under reflux for three hours, protected by a blanket of nitrogen. The solvent is removed and the residue is dissolved in chloroform. The resulting solution is washed with 10% aqueous sodium bisulfite solution and then with 5% potassium hydroxide followed by water. The solution is dried over sodium sulfate and concentrated under reduced pressure to give 9a,22-difluoro-20-spirox-4,6-diene 11,3 ol-3,21 dione, which has the following structure:

Example 20 A solution of 80 mg. of 9a,22-difluoro-20-sp-irox-4,6-

diene-11,8-ol-3,21-dione in 1.0 ml. of thioacetic acid is heated under reflux on a steam bath for a period of /2 hour. Excess thioacetic acid is evaporated in a stream of nitrogen. Trituration with ether affords crystals which, after two recrystallizations from a mixture of acetone and hexane, gives 7a-acetylthio-9a,22-difluoro-20-spirox-4-ene- 1l,B-ol-3,21-dione, which has the following structure:

Example 21 To 8.0 g. of 22-fiuoro-Z0-spirox-4-ene-3,21-dione-9,11B- oxide suspended in 100 ml. of t-butyl alcohol is added 3.2 g. of commercial (95%) sodium methylate. To this mixture under nitrogen is added 5 ml. of diethyl oxalate, and the mixture is then stirred under nitrogen for 6 hours. Complete solution occurs and the product precipitates within 10 minutes. Addition of ether followed by filtration gives 13 g. of the sodium enolate, which is a powder, soluble in water but insoluble in dilute acid.

A mixture of the crude sodium enolate, 13 g. of anhydrous potassium carbonate, 300 ml. of acetone and 50 ml. of methyl iodide is refluxed for 20 hours, filtered while hot and the filtrate concentrated to a small volume. A large amount of water is added to the concentrate which is then extracted with ethyl acetate. The extract is washed with saturatedsodium chloride solution, dried and treated with activated carbon. After evaporation 7.8 g. of a pale yellow residue is obtained.

To this residue, dissolved in 250 ml. of absolute alcohol, is added 1.0 g. of 95% sodium methylate. The mixture is then allowed to stand at room temperature for 4 hours. After the addition of a few drops of acetic acid and 20 ml. of Water, the methanol is removed under reduced pressure at a temperature not exceeding 35 C. The ethyl acetate extract of the mixture is washed to neutrality with a saline solution, dried, and decolorized with activated carbon. Evaporation leaves 5.7 g. of the crude 2a-methyl-22-fluoro-20-spirox-4-ene 3,21 dione- 9,11fi-oxide, which has the following structure:

Example 22 To a solution of 200 mg. of 2a-methyl-22-fluoro-20- spirox-4-ene-3,21-dione-9,1lfl-oxide in 2 ml. of chloroform and 2 m1. of tetrahydrofuran in a poly-ethylene bottle at 60 C. is added 2 ml. of a 2:1 (by weight) mixture of anhydrous hydrogen fluoride and tetrahydrofuran. After 4 hours at -10 C. the mixture is cooled to ---60 C. and cautiously added to a stirred mixture of 30 ml. of 25% aqueous potassium carbonate and 25 ml. of chloroform kept at -5 C. The aqueous phase is further extracted with chloroform and the latter phase is washed with water and dried over magnesium sulfate. The residue on crystallization from a mixture of acetone and ether gives 2a-methyl-9 ,22-difluoro 20 spirox-4-ene-11p-ol- 3,21-dione, which has the following structure:

Example 23 To mg. of 2a-methyl-9a,22-difluoro-20-spirox-4- ene-11fl-ol-3,21-dione in 5 ml. of t-butanol and 0.1 ml. of acetic acid is added 50 mg. of selenium dioxide. The mixture is refluxed under nitrogen for 18 hours; then 50 mg. of selenium dioxide is added and the mixture is refluxed anadditional 24 hours. The product is filtered, and the filtrate evaporated to dryness. The residue is extracted with ethyl acetate and the extract is washed successively with aqueous sodium bicarbonate, ammoniumsulfide, dilute ammonia Water, water, dilute hydrochloric acid and water, and then dried over magnesium sulfate. The extract is treated with activated charcoal and then concentrated to dryness. Crystallization of the residue from a mixture of acetone and ether gives 2- methyl-9a,22-di-fiuoro-20-spirox-1,4 diene 11fl-ol-3,21- dione, which has the following formula:

Cat

Example 24 Example 25 g e A solution of 80 mg. of 2a-methyl-9u,22 difiuoro-20- spirox-v4,6-diene-1lfi-ol 3,2l-dione in 1.0 m1. of thioacetic acid is heated underrefiux on a steam bath for a period of /2 hour. Excess thioacetic acid is evaporated in a stream of nitrogen. Tritura-ti-on with ether affords crystals which, after two recrystallizations from a mixture of acetone and hexane, gives 5.() mg. of pure laacetylthio-Zamethyl 911,22 difluoro 20 spirox 4 ene 11,8 o1 3,2l-d-ione, which has the following structure:

cm 7 i l o F i Q: V--S-Y OHI Example26 A mixture of 1.5 parts by weight of 22-fluoro-20-spirox- 4,6-diene-3,21-dione and 1.5 parts by volume of thiopropionic acid is heated on the steam bath for 3 hours. After standing overnight, the reaction mixture is diluted with 25 parts by volume of ether. The crystals which form on cooling are separated and recrystallized from ether and petroleum ether to obtain 7a-propionylthio- 22-flu'oro-20-spirox-4-ene-3,2l-dione which has the following structure:

MMF

O= S-COCHzCH;

Example2 7 I A solution of 3 millimoles of 3-ethylenedioxy-22-methoxalyl-20-spi-rox-5-ene-2l-one, and 3.05 millimoles of pyridine in 25 ml. of dry benzene is cooled to 0 C. To this solution is added slowly with stirring 3 millimoles of bromine in-25' ml. of benzene. The reacting mixture is allowed to Stand for :minutes at room temperature V oxalyl-ZO-spirox-5-ene-2l-one, and 3.05 mi-llimoles of pyand is then poured into water and ether. The organic solvent layer is washed several times with water, dried and then evaporated in vacuo at a temperature less than 35 C. The residue is taken up in 35 ml. of dry methanol cooled to 0' C. and 2 ml. of 2 N sodium methoxide in methanol is then added. The mixture is allowed to stand at room temperature for 2 hours and is then acidified with aqueous sodium dihydrogen phosphate in the cold. Mostoi the solvent is then removed in vacuo and the residue is extracted with ether. The ether extract is washed, dried and concentrated in vacuo to give the crude 3-ethylenedioxy-22=bromo-20-spirox-5-ene-2l-one, which is suitable for the next step of the synthesis without further purification, and has the formula:

1 [ZUJ Example 28 A solution of 3 m-illimoles of 3-ethylenedioxy-22-methridine in 25- ml. of dry benzene is cooled to 0 C. To this solution is added slowly with stirring 3 millirnoles of chlorine in 25 m1. of benzene. The reacting mixture is allowed to stand for 15 minutes at room temperature and is then poured 'intowater and ether. The organic solvent layer is washed several times with water, dried and then evaporated in vacuo at a temperature less than 35 C. The residue is taken up in 35 ml. of dry methanol cooled to 0 C. and 2 ml. of 2 N sodium methoxide in methanol is then added. The mixture is allowed to stand at room temperature for 2 hours and is then acidified with aqueous sodium dihydrogen phosphate in the cold. Most of the solvent is then removed in vacuo and the residue is extracted with ether. The ether extract is washed, dried and concentrated in vacuo to give the crude 3-ethylenedioxy-22-chloro-20-spirox-5-ene-2l-one, which is suitable for the next step of the synthesis without further purification, and has the formula:

0-1 7 NW Cl Seventy thr'ee milligrams of 3-ethylenedioxy-22-bromo- 20-spirox-5-ene-21-one is dissolved in 4 cc. of acetone and 5 mg. of p-toluenesulfonic acid monohydrate in 1 cc. of acetone is added. The solution is allowed to stand overnight at room temperature. It is then diluted with water and extracted three times with ether. The combined ether extracts are washed with Water, dried and concentratedin vacuo. The residue is chromatographed over acid-washed. alumina and eluted with mixtures of chloroform and ether. Recrystallization from a mixture of methylene chloride and ether affords 22-bromo-20- spirox- -t-ene-3,2l-diohe, which has -the formula:

A suspension" of 22-bromo-20-spirox-4-ene-3,2l-dione (11.1 g.) and chloranil (24.3 g.) in 360 ml. of dry t-butanol is heated under reflux for three hours, protected by a blanket of nitrogen. The solvent is removed and the residue is dissolved in chloroform. The resulting solutionis washed successively with 10% aqueous sodium bisulfite solution, potassium hydroxide and then water. The solution is dried over sodium sulfate and concentrated under reduced pressure to give 22-bromo-20- spirox-4,6-diene'-3,2l-dione, which has the formula:

In accordance with the above procedure, but starting 1 .with 22-chloro-20-spirox4,'6-diene-3,21-dione in place .of 22 bromo-20-spirox 4-ene-3,2l-dione there is 7 obtained 7a-acetylthio-22-chloro-20-spirox-4-ene-3,2l-dione.

l 8 Example 31 A mixture of 1.850 g. of 20-spirox-4-ene-lIdol-3,21- dione, cc. of butanone dioxolane (distilled from lithium aluminum hydride) and 60 mg. of p-toluene-sulfonic acid monohydrate is distilled for 4% hours through a Vigreux column. The residue is partitioned between 5% aqueous sodium bicarbonate and benzene. The organic solvent layer is washed with water and dried, and the solvent is removed in vacuo. The residue is chromatographed over 50 guts. of acid-washed alumina and eluted with mixtures of ether and chloroform to give Z a-ethylenedioxy-20-spirox-5 ene-llfl-ol-Zl-one, which has the following structure:

Example 32 Dimethyl' oxalate (3.5 gms.) is dissolved-in 30 cc. of benzene. The solution is then azeotropically dried to a volume of 25 cc. Sodium hydride (1.050 g.), as a 52.7%

dispersion in oil, is added. A slight reaction occurs. To this grey suspension is added 687 mg. of S-ethylenedioxy- 20-spirox-5-ene-llB-ol-Zl-one. The reaction'mixture is held at 40 C. overnight with magnetic stirring. It is then diluted with an equal volume of ether and centrifuged. The precipitate is washed three times with an equal volume of ether. The sodium enolate is then covered with about 10 cc. of benzene and a saturated solution of sodium dihydrogen phosphate (pH 4) is added as quickly as possible. The separated aqueous layer is extracted two more times with ether. The combined organic layers are dried and concentrated in vacuo. The product is recrystallized several tirries from a mixture of ether and petroleum ether to give 3-ethylenedioxy-2'2-methoxallyl- 20-spirox-5-ene-l lfi ol-Zl-one, which has the following structure:

HO \A Example 33 A solution of 100 mg. of 3-ethylenedioxy-22-methoxalyl- ZO-spirox-S-ene-l'lB ol-Zl-one, dissolved in 6 cc. of pyridine, is cooled to 0 C. Sodium ethoxide 0.26 cc. of 1 M sodium ethoxide in ethanol is then added and the resultant solution is flushed with nitrogen for about 2 minutes. With operations conducted behind a shield, perchloryl fluoride is then bubbled into the reaction mixture for 15 minutes at 0 C. and the system is again flushed with nitrogen for about two minutes. The mixture is then poured into water and extracted with ether. The combined ether layers are washed with water and dried, and the solvent evaporated at room temperature using a rotary evaporator. Final traces of solvent are removed under vacuum.

1 9 It The residue is dissolvedin 4 cc. of absolute ethanol, and 1 cc. of 1 M sodium ethoxide in ethanol is added.

, The solution is then allowed to stand at room temperature tion.

Example 34 Seventy-three milligrams of 3-ethylenedioxy-22-fluoro- 20-spirox-5-ene-11fi-ol-21-one is dissolved in 4 cc. of acetone and 5 mg. of p-toluenesulfonic acid monohydrate in 1 cc. of acetone is added. The solution is allowed to stand overnight at room temperature. It is then diluted with water and extracted three times with ether. The combined ether extracts are washed with water, dried and concentrated in vacuo. The residue in chromatographed over acid-Washed alumina and eluted with mixtures of chloroform and ether. Recrystallization from a mixture of methylene chloride and ether afiords 22-fluoro-20- spirox-4-ene-1lfi-ol-3,21-dione, which has the following structure:

Example 35 Example 36 A solution of 80 mg. of 22-fluoro-20 spirox-4,6-diene- 11B-ol-3g21-dion'e in 1.0 ml. of thioacetic acid is heated under reflux on a steam bathfor a period of A hour. Excess thioacetic acid is evaporated in a stream of nitrogen. Trituration with ether affords crystals which, after two rccrystallizations from a mixture of acetone and hexane, gives 7a-acetylthio-22-fluoro-20-spirox-4-ene-11 8- ol-3,21-dione, which has the following formula:

In accordance with the above procedure, but starting with 22-fluoro-20-spirox-4,6-diene-3,11,21-trione in place of the 22-fluoro-20-spirox-4,6-diene-l1,8-ol-3,2l one, there is obtained 7m-acetylthio-22-fluoro-20-spirox-4-ene-3,11,

I 21-trione.

Example 37 To mg. of 22-fluoro-20-spirox-4-ene-l118-01-331- dione in 5 ml. of t-butanol and 0.1 ml. of acetic, acid is added 50 mg. of selenium dioxide. The mixture is reflnxed under nitrogen for 18 hours; then 50 mg. of selenium dioxide is added and the mixture is refluxed an additional 24 hours. The mixture is filtered, and the filtrate evaporated to dryness. The residue is extracted with ethyl acetate and the extract is washed successively with aqueous sodium bicarbonate, ammonium sulfide, dilute ammonia water, water, dilute hydrochloric acid and water, and then dried over magnesium sulfate. The extract is treated with activated charcoal and then concentrated to dryness. Crystallization of the residue from a mixture of acetone and ether gives ZZ-fluoro-ZO-spirox-1,4-diene- 1lfl-ol-3,2l-dione, which has the following formula:

Example 38 A solution of 400 mg. of 22-fluoro-20-spirox-4-ene- 1'1,6-ol-3,21-dione in 4 m1. of pyridine is added to the complex formed by the addition of 400 mg. of chromium trioxide to 4 ml. of pyridine. The mixture is swirled until thoroughly mixed and then allowed to stand at room temperature overnight. The reaction mixture is poured into water, and the aqueous mixture is extracted with ether and then twice with ethyl acetate. The combined ether and ethyl acetate extracts are washed with dilute aqueous sulfuric acid at about 0 C., and then with water until neutral. The organic solvent layer is then dried, the solvents are evaporated therefrom in vacuo, and the following structure:

Oj- MN F In accordance with the above procedure, but starting with the following compounds in place of 22-fluoro-20- spiroX-4-ene-11fi-ol-3,2l-dione, there is obtained the corresponding ll-keto-steroid:

7a-acetylthio 911,22 difiuoro-20-spirox-4-ene-l113-01- 3,2l-dione 9a,22-difiuoro-20-spirox-1,4-diene l 1153-01-3 ,2 l-dione 2a methyl-9a,22-difluoro-20-spirox-4-ene-1 113-01-321- dione 7a-acetylthio 2oz methyl 9a,22 difluoro-20-spirox- 1 1 fl-ol-3,21-dione Z-methyl 901,22 difluoro 20-spiroxl,4-diene-11118-01- 3,21-dione.

Various changes and modifications may be made in carrying out the present invention without departing from the spirit and scope thereof. Insofar as these changes and modifications are within the purview of the annexed claims, they are to be considered as part of our invention.

We claim:

1. 3-ethylenedioxy-20-spirox-5-ene-21-one.

2. 3-ethylenedioxy-22-halo-20-spirox-S-ene-21-one.

3. The process which comprises reacting a compound of the formula:

O= -iL-OCHA wherein X has the significance aboved defined.

4. The process which comprises reacting a compound 22 of the formula:

O -w iB-ill-OCH;

wherein the dotted line between carbon atoms 9 and 11 indicates that -a double bond may be present in this position and wherein X is a member of the group consisting of hydrogen and hydnoxy, sequentially with bromine in the presence of an organic base, and then with an alkali metal alkoxide to form a compound of the formula:

wherein X has the significance aboved defined.

5. The process which comprises reacting a compound of the formula:

wherein X has the significance aboved defined.

References Cited in the file of this patent UNITED STATES PATENTS Dodson et :al Nov. 4, 1958 OTHER REFERENCES Ringold ct 'al.: J. Org. Chem. 21, pages 239-40, 1956.

Chemical and Engineering News, September 16, 1957, pages 66-67.

Loewenth-al: Tetrahedron, vol. 6, No. 4, June 1959, page 290. 

2. 3-ETHYLENEDIOXY-22-HALO-20-SPIROX-5-ENE-2-ONE. 